This invention relates to method for increasing the solubility of a transcriptase inhibitor composition and a transcriptase inhibitor composition prepared in accordance with such a method. More particularly, but not exclusively, this invention relates to a method for increasing the solubility of nevirapine to increase the bioavailability and efficacy thereof. This invention further relates to new forms of nevirapine.
The present invention further relates to novel crystalline forms of 11-cyclopropyl1-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b: 2′,3′-e][1,4]diazepin-6-one, generically known as nevirapine. More specifically, the present invention provides novel microspherical and/or nanospherical Form-V and crystalline Form-VI of nevirapine.
Nevirapine is a well-known anti-retroviral drug used in the treatment of HIV-1 infection and AIDS. It is a non-nucleoside reverse transcriptase inhibitor and, structurally, it is a member of the dipyridodiazepinone chemical class of compounds.
A first disadvantage experienced with commercially available nevirapine is that it is highly hydrophobic and very poorly water soluble. Although comprehensive solubility and permeability data for nevirapine is lacking, the FDA classifies nevirapine as a Class II (high permeability, low solubility) drug. nevirapine's water solubility at neutral pH is ˜1 mg/ml, and is only highly soluble at pH<3.
Nevirapine is currently available in two dosage forms, namely tablets (anhydrous form) and in suspensions (hemi-hydrate form). The mean maximum particle sizes of commercially available nevirapine are generally larger than 50 μm.
A further disadvantage experienced with nevirapine is that there are no parenteral dosage forms available, because of the relatively large particle size and poor water solubility. Particle sizes of commercially available nevirapine raw materials are unsuitable for parenteral administration in suspension. Further owing to the particle sizes, nevirapine in inhalant and transdermal dosage forms are also not available.
Yet another disadvantage experienced with known forms of nevirapine is that bioavailability thereof decreases at higher doses due to absorption being solubility rate-limited.
US patent application number 2005/0059653 describes crystalline Form-II and Form-III of nevirapine. A disadvantage of both these forms is that they are also suffering from poor solubility.
Applicant is the co-applicant of a separate patent application in respect of another form of nevirapine, namely Form-IV. The novel forms of nevirapine referred to herein are thus designated Form-V and Form-VI respectively.